ABSTRACT: Up to 90% of cancer survivors report insomnia or some form of sleep quality impairment (SQI) post-treatment which co-occurs with dysregulated circadian rhythm, impaired physical function, chronically up-regulated inflammatory responses, and, when severe, increased cancer morbidity and mortality. Despite the ubiquity of insomnia and SQI, they are under-diagnosed and under-treated in cancer survivors. Yoga is a well-tolerated exercise intervention with promising preliminary evidence for its efficacy in improving insomnia and SQI. Our previous multicenter, phase III, randomized, controlled, trial (RCT) in 410 cancer survivors from 12 community oncology practices in the U.S., showed that our standardized yoga intervention (YOCAS(c)(R): 4 wks, 2x/wk, 75 min/sess) produced moderate to large improvements in insomnia and SQI while also improving circadian activity rhythms. Yoga participants also decreased, while control participants increased, sleep medication use. Adherence to YOCAS(c)(R) was good (80%) with no study-related adverse events, and 100% of participants found YOCAS(c)(R) useful and would recommend it to other survivors. The next logical empirical steps, in line with NCI research priorities to develop effective, evidence-based, supportive care interventions for survivors, are to compare the YOCAS(c)(R) intervention to a gold-standard treatment (i.e., Cognitive Behavioral Therapy for Insomnia [CBT-I]) and a time and attention placebo control. Therefore, we propose to conduct a multicenter, 3-arm, blinded, phase III RCT comparing the effect of Arm 1) our YOCAS(c)(R) program, Arm 2) CBT-I, and Arm 3) a health education control on insomnia in 630 cancer survivors 6-12 months following adjuvant treatment using valid measures and analytical techniques. YOCAS(c)(R) and CBT-I will be delivered in groups using standard effective clinical formats (i.e., YOCAS(c)(R) = 2x/wk in 75-minute sessions over 4 weeks; CBT-I 1x/wk in 90-minute sessions over 8 weeks). Health education will also be delivered in groups and matched for equal time and attention to YOCAS(c)(R). We will require participants to meet DSM-IV insomnia criteria and the clinical cut off score for insomnia of >10 on the Insomnia Severity Index (ISI), assess the 3- and 6-month sustainability of insomnia benefits, and examine possible conceptually based biological mechanisms (circadian activity rhythms, physical function, and inflammation) that may influence insomnia via YOCAS(c)(R). We hypothesize YOCAS(c)(R) will be as effective as CBT-I and more effective than health education for improving insomnia, SQI, circadian activity rhythms, physical function, and inflammation; insomnia improvements will be sustained 3 and 6 months later in the YOCAS(c)(R) and CBT-I groups but not in the health education group; and changes in circadian activity rhythms, physical function, and inflammation will mediate the effects of YOCAS(c)(R) on insomnia. This is the first phase III, blinded RCT to test: 1) the effectiveness of YOCAS(c)(R) compared to CBT-I and a health education control for improving insomnia and SQI, 2) the 3- and 6-month sustainability of insomnia benefits from YOCAS(c)(R), and 3) the role of specific biological mediators in the efficacy of YOCAS . (c)(R)